Structure-based evidence for the enhanced transmissibility of the dominant SARS-CoV-2 B.1.1.7 variant (Alpha)

Xia, Shuai; Wen, Zuoling; Wang, Lijue; Lan, Qiaoshuai; Jiao, Fanke; Tai, Linhua; Wang, Qian; Sun, Fei; Jiang, Shibo; Lu, Lu; Zhu, Yun

doi:10.1038/s41421-021-00349-z

Cited by 22 publications

(20 citation statements)

References 14 publications

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“…It was demonstrated that the D570 residue is capable of forming an interprotomer hydrogen bond with N856, effectively re-establishing the bond that stabilizes this “down” confirmation [ 44 ]. Within the S trimer, when D1118H mutation occurs, the three histidine residues (one from each monomeric S) form a histidine triad within the trimer, stabilizing the overall structure of the trimeric S complex [ 45 ]. Although there is, as yet, no direct evidence of the role this stabilization plays, it was suggested that this effect may compensate for local destabilizations caused by associated mutations such as T716I [ 44 ].…”

Section: Mutations Of the S2 Subunitmentioning

confidence: 99%

Mutations and Evolution of the SARS-CoV-2 Spike Protein

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Zhang

et al. 2022

Viruses

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The SARS-CoV-2 spike protein mediates target recognition, cellular entry, and ultimately the viral infection that leads to various levels of COVID-19 severities. Positive evolutionary selection of mutations within the spike protein has led to the genesis of new SARS-CoV-2 variants with greatly enhanced overall fitness. Given the trend of variants with increased fitness arising from spike protein alterations, it is critical that the scientific community understand the mechanisms by which these mutations alter viral functions. As of March 2022, five SARS-CoV-2 strains were labeled “variants of concern” by the World Health Organization: the Alpha, Beta, Gamma, Delta, and Omicron variants. This review summarizes the potential mechanisms by which the common mutations on the spike protein that occur within these strains enhance the overall fitness of their respective variants. In addressing these mutations within the context of the SARS-CoV-2 spike protein structure, spike/receptor binding interface, spike/antibody binding, and virus neutralization, we summarize the general paradigms that can be used to estimate the effects of future mutations along SARS-CoV-2 evolution.

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Section: Mutations Of the S2 Subunitmentioning

confidence: 99%

Mutations and Evolution of the SARS-CoV-2 Spike Protein

Magazine

Zhang

et al. 2022

Viruses

170

110

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“…1f ). These variants exhibit enhanced transmission, pathogenicity, immune escape, or a combination of all three, and different countries can have different dominant variants 27 . Variant viruses always encoded spike proteins with substitutions in antibody binding hot spots.…”

Section: Resultsmentioning

confidence: 99%

Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies

et al. 2022

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The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed that CTSL cleavage promoted S to adopt receptor-binding domain (RBD) “up” activated conformations, facilitating receptor-binding and membrane fusion. We confirmed that CTSL cleavage is essential during infection of all emerged SARS-CoV-2 variants (including the recently emerged Omicron variant) by pseudovirus (PsV) infection experiment. Furthermore, we found CTSL-specific inhibitors not only blocked infection of PsV/live virus in cells but also reduced live virus infection of ex vivo lung tissues of both human donors and human ACE2-transgenic mice. Finally, we showed that two CTSL-specific inhibitors exhibited excellent In vivo effects to prevent live virus infection in human ACE2-transgenic mice. Our work demonstrated that inhibition of CTSL cleavage of SARS-CoV-2 S protein is a promising approach for the development of future mutation-resistant therapy.

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“…And the transmission rate of B.1.1.7 increased with age and viral load ( Lyngse et al, 2021 ). It was found that the mutations in the B.1.1.7 S protein had multiple structural effects and could significantly improve its viral fusion activity and infectivity ( Xia et al, 2021 ). As SARS-CoV-2 continues to circulate globally, more SARS-CoV-2 variants have emerged including VOC Beta (B.1.351 lineage, etc.)…”

Section: Discussionmentioning

confidence: 99%

Mutations and Phylogenetic Analyses of SARS-CoV-2 Among Imported COVID-19 From Abroad in Nanjing, China

et al. 2022

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic and is threatening human health globally. The rapid genome sequencing and bioinformatic analysis of SARS-CoV-2 have become a helpful tool in the battle against the COVID-19. Here, we report the genetic characteristics, variations and phylogenetic analysis of SARS-CoV-2 sequenced from 42 clinical specimens. The complete genomes sequencing of SARS-CoV-2 were performed using Oxford Nanopore sequencing. All genomes accumulated mutations compared to the Wuhan-Hu-1 (GenBank Accession No: MN908947.3). Our data of the 42 whole genomes revealed 16 different lineages. The B.1.1 lineage was the most frequent, and 5, 2, 2, 3, and 1 sequences were classified as lineages of B.1.1.7, B.1.351, P.1, B.1.617.2, and C.37, respectively. A total of 328 nucleotide mutation sites were found in 42 genomes, among which A23403G mutation (D614G amino acid change in the spike protein) was the most common substitution. The phylogenetic trees of 42 SARS-CoV-2 sequences and GISAID-available SARS-CoV-2 sequences were constructed and its taxonomic status was supported. These results will provide scientific basis for tracing the source and prevention and control of SARS-CoV-2 imported from abroad in Nanjing, China.

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Structure-based evidence for the enhanced transmissibility of the dominant SARS-CoV-2 B.1.1.7 variant (Alpha)

Cited by 22 publications

References 14 publications

Mutations and Evolution of the SARS-CoV-2 Spike Protein

Mutations and Evolution of the SARS-CoV-2 Spike Protein

Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies

Mutations and Phylogenetic Analyses of SARS-CoV-2 Among Imported COVID-19 From Abroad in Nanjing, China

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